This revised competitive renewal continues our research into the role of the vitamin D receptor (VDR) in regulating the response to the active hormone, 1,25-dihydroxyvitamin D3 (calcitriol). The dual themes of our research are to study the role of the VDR in calcitriol action and to elucidate mechanisms of resistance to calcitriol. Our goals are to translate knowledge of VDR action to clinical applications and improve calcitriol therapy as an anti-proliferative and pro-differentiating hormone for use in the treatment of osteoporosis, rickets, cancer, etc. The grant has two Specific Aims, both related to calcitriol action and mechanisms of VDR resistance. Preliminary data indicate that both of the Aims are feasible. Aim I continues our study of children with Hereditary Vitamin D Resistant Rickets (HVDRR) a disease due to mutations in theVDR1 causing extreme resistance to the action of calcitriol. Sub-Aims will: (a) analyze new cases of HVDRR, (b) develop methods to bypass the resistance and rescue the VDR defect, and (c) analyze the gene expression profile in mutant and normal skin fibroblasts. Aim II is a study of the interaction of the VDR with Hairless (HR), a recently recognized co-repressor of the VDR. Mutations in the hairless gene cause a syndrome of alopecia with papular lesions (APL) that is virtually identical to the alopecia in HVDRR. Studies include an examination of VDR and HR interactions with emphasis on HVDRR mutants. Sub-Aims include (a) studies of the role of HR as a VDR suppressor and regulator of VDR function, (b) the role of various isoforms of HR, (c) VDR and HR interactions in HVDRR, and (d) in APL mutants, (e) mechanisms by which HR leads to VDR stabilization, (f) regulation of HR and (g) search for HR binding proteins. Our lab group has substantial skills in these studies and multiple collaborators will add their expertise. The grant is a substantial undertaking examining many aspects of VDR function, all directed towards understanding calcitriol/VDR action and hormone resistance. The significance will be to develop and employ cells harboring natural mutations in VDR and HR as ideal reagents that allow interogation of the step by step mechanism of action of calcitriol. By elucidating how cells become resistant to the action of calcitriol we hope to develop strategies to overcome the resistance and develop improved treatment for children with HVDRR or APL as well as to find ways to enhance calcitriol action to potentially treat diseases such as osteoporosis, cancer and psoriasis.